The development of new forms of therapeutics that use macromolecules such as proteins or nucleic acids as therapeutic agents has created a need to develop new and effective approaches of delivering such macromolecules to their appropriate cellular targets. Nanoparticle technology has found application in pharmacology and drug delivery.
Nanocarriers have been developed for macromolecule delivery, including polymers, liposomes, and inorganic nanoparticles such as silica nanoparticles. Among various silica nanomaterials, the hollow silica nanoparticles (HSNs) have been deemed to have great potential as drug delivery systems due to their unique physical/chemical properties, such as large pore volume, chemical/thermal stability, high loading capacity, adjustable surface properties and excellent biocompatibility. Different from common solid mesoporous silica nanoparticles (MSNs), HSNs can encapsulate species that are large in size (such as bioactive ingredients) and exhibit higher loading capacity of said large species due to the unique morphology, i.e., thin porous shell and hollow interior space, which in turn enhance the efficacy of applications in catalysis, biomedicine, etc. The morphology and characteristics of HSNs greatly depend on the synthetic strategies, which differ from application to application.
Hard-templating methods, known as conventional methods for synthesizing hollow silica nanoparticles, utilize solid and rigid particles (such as polystyrene particles) as a core template, and the material of the template is heterogeneous to silica. Given this, the core template can be etched by calcination, solvent dissolution or other means to leave a hollow space inside the closed silica shell (Li, Y.; Shi, J. Hollow-structured mesoporous materials: chemical synthesis, functionalization and applications. Adv Mater 2014, 26, 3176-3205). Though the homogeneity of the nanoparticle size, nanoparticle shape and dimension of the cavity can be precisely controlled, such methods require a multistep synthetic process as well as a tedious template etching procedure, which is time-consuming and/or complicated.
Soft-templating methods also utilize the concept of etching the core template from a core-shell structure to form hollow silica nanoparticles, but the core template is “softer” than those applied in the hard-templating methods. For example, the soft core templates can be flexible liquid “particles,” such as micelles, emulsion, vesicles consisting of materials heterogeneous silica, or even gas bubbles. However, it is generally considered that HSNs prepared by these methods have an irregular appearance and wider particle size distribution due to the flexibility of the soft template. For example, special Kippah-like HSNs will be formed if the oil in the oil-in-water (O/W) emulsion escapes through mesopores before the silica shell structure becomes rigid (Tsou, C.-J.; Hung, Y.; Mou, C.-Y. Hollow mesoporous silica nanoparticles with tunable shell thickness and pore size distribution for application as broad-ranging pH nanosensor. Microporous and Mesoporous Materials 2014, 190, 181-188).
However, the bioactive ingredients cannot be loaded prior to the template etching procedure because said procedure would likely destroy the activity thereof.
In addition to the above-mentioned methods, structural-difference selective etching methods provide a different concept for synthesizing hollow silica nanoparticles. In such methods, different silica sources are used to form silica nanoparticles having structural difference within the nanoparticles, i.e., the structure would exhibit different strengths at different sites, in particular the inner layers would be more fragile than the outer layers. Such phenomenon was found in some sol-gel processes, including the most general Stöber method. Hence, by selectively and gently removing the fragile parts of the nanoparticles, a hollow space would be created. The selective removal of the fragile parts could be relatively controllable, in particular when the level of structural difference is raised by specific designs during the fabrication of the silica nanoparticles.
By taking advantages of synthesis in a microemulsion system, a method of de novo enzyme encapsulation in HSNs has been disclosed by Chang, et. al. (Enzyme encapsulated hollow silica nanospheres for intracellular biocatalysis. ACS Appl Mater Interfaces 2014, 6, 6883-6890; Intracellular implantation of enzymes in hollow silica nanospheres for protein therapy: cascade system of superoxide dismutase and catalase. Small 2014, 10, 4785-4795). However, though structural-difference selective etching methods may somehow prevent the problems confronted by using hard- or soft-templating methods, the yield of the hollow silica nanoparticles is quite low (up to about 10 mg/20 mL oil). In addition, the nanoparticles prepared by these methods still tend to aggregate, which is a significant problem to be solved.
Hence, there is still needs for improved hollow silica nanoparticles as drug delivery systems and a simple, cost-effective way to synthesize such hollow silica nanoparticles.